rs2229443

chr12-6121280-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000552.5(VWF):c.114C>T(p.Phe38=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,614,186 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (20 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.229

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 12-6121280-G-A is Benign according to our data. Variant chr12-6121280-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310090.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr12-6121280-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.229 with no splicing effect.
• BS2: High AC in GnomAd at 350 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.114C>T	p.Phe38=	synonymous_variant	3/52	ENST00000261405.10
VWF	XM_047429501.1	c.114C>T	p.Phe38=	synonymous_variant	3/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.114C>T	p.Phe38=	synonymous_variant	3/52	1	NM_000552.5	P1
VWF	ENST00000321023.5	c.*173C>T		3_prime_UTR_variant, NMD_transcript_variant	4/7	1
VWF	ENST00000538635.5	n.143C>T		non_coding_transcript_exon_variant	3/6	4
VWF	ENST00000538563.1	c.*173C>T		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00230 AC: 578 AN: 251250 Hom.: 0 AF XY: 0.00232 AC XY: 315 AN XY: 135796

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00384 AC: 5610 AN: 1461872 Hom.: 20 Cov.: 34 AF XY: 0.00373 AC XY: 2714 AN XY: 727232

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74486

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00320 Hom.: 0

Bravo AF: 0.00218

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	VWF: BP4, BP7 -

Hereditary von Willebrand disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 29, 2016

- -

VWF-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	2.2
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229443; hg19: chr12-6230446; COSMIC: COSV54620737; COSMIC: COSV54620737;